It is clear that opioid receptors play a role in the regulation of the immune response, including resistance to a number of infectious agents. The opioids modulate the expression of chemokines and chemokine receptors which are critical both for normal immune responses, as well as for the host-parasite interactions associated with AIDS. It has become clear that the opioids can alter susceptibility to infection by HIV. We propose studies in this grant application which should provide a better understanding of the nature of the effects of opioids on the immune system. It is our hypothesis that the opioids selectively alter the production of cytokines that in turn regulate critical chemokine and chemokine receptor expression. We propose studies to clarify the mechanism(s) of the opioid-modulation of essential chemokines and their receptors, with particular emphasis on chemokines which are likely to play a role in susceptibility to infection by HIV. Our findings suggest that an important part of the modulation of immune function by the opioids is to promote the expression of transforming growth factor-beta (TGFbeta), a cytokine which plays an important role in the regulation of virtually all cells of the immune system. We intend to examine the molecular basis for the induction of TGFbeta by the opioids. We also propose to evaluate the molecular mechanisms involved in the TGFbeta-modulation of chemokine and chemokine receptor expression. We expect the proposed studies will enhance our understanding of the role of opioid drugs of abuse in the interaction of the immune system with HIV.